The objectives in this study are to: 1) determine the nature and mechanism of the functional activation of neutrophils (PMN) by chemotaxis; 2) determine which human lymphocyte subpopulations can respond to chemotactic factors as well as what chemotactic factors are produced in vivo; and 3) determine how leukocyte chemotaxis may be regulated by prostaglandin E (PGE), and humoral factors produced as a result of disease. Our preliminary studies have shown that human PMNs have enhanced bactericidal and chemiluminescence activity following chemotaxis. In this proposal we will define the nature and mechanism of activation using functional (chemiluminescence, bactericidal and antibody dependent tumoricidal assays), morphologic (electron microscopy), C-AMP, C-GMP analysis, and surface receptor analysis for Fc, complement and lectin receptors. Human lymphocyte subpopulation chemotaxis will be determined using an in vitro casein mediated chemotaxis technique and purified B, T, T mu and T gamma lymphocytes isolated by rosette depletion techniques currently performed here. Potential lymphocyte chemotactic factors will be produced by stimulating human lymphocytes, monocytes, and granulocytes with mitogen, antigen or zymosan. Additional studies will be performed with other known leukocyte chemotactic factors as well as tests with lymphocyte rich synovial fluids from arthritis patients. Finally, studies on potential mechanisms to regulate leukocyte chemotaxis will include: the comparative effects of prostaglandin E2 on human lymphocyte, PMN, and monocyte chemotaxis; studies on the mechanism by which polymeric myeloma IgA paraproteins inhibit leukocyte chemotaxis by analyzing their effect on C-AMP and C-GMP levels as well as the the inhibitory effects of isolated IgA-Fc fragments; and Finally, characterization of a heat stable humoral factor resulting from chronic hemodialysis which can inactivate the chemotactic activity of C5a. These studies will aid in our understanding of how cells migrate to an inflammatory site, how they function once there, and how the process is regulated by humoral substances.